Amyotrophic Lateral Sclerosis (ALS) is one of the most devastating neurological diseases leading to death typically in 3 years of onset. Treatment is severely limited, and no cure is available. Oxidative stress and mitochondrial dysfunction have been implicated in ALS pathophysiology. Coenzyme Q 10 (CoQ 10), a mitochondrial cofactor and powerful antioxidant, prolongs survival in the transgenic ALS mouse model and slows functional decline in other human neurodegenerative disease. CoQ 10 is a nonprescription dietary supplement with an excellent safety profile and central nervous system penetration. Thus, we propose to conduct a 2-stage phase II, randomized, placebo-controlled, double-blind, multi-center clinical trial of high-dose, solubilized CoQ 10 against placebo (target enrollment 185 patients at 18 clinical sites). This project will test the hypothesis that CoQ 10 reduces functional decline in patients with ALS. Aim 1 will consist of two stages. Stage 1 identifies which of two CoQ 10 doses is preferable (1000 mg. or 2000 mg. daily). Stage 2 compares the selected dose against placebo to assess whether evidence of efficacy is sufficient to justify proceeding to a future phase III trial. The primary outcome measure is the change in ALS Functional Rating Scale revised (ALSFRSr) score from baseline (randomization) to 9 months. We chose the ALSFRSr because: (1) It measures daily living functional abilities, a clinically meaningful outcome; (2) it is a validated predictor of survival; and (3) its ease of administration will minimize subject dropout. Aim 2 will determine whether CoQ 10 affects secondary measures: (1) forced vital capacity, (2) fatigue severity, (3) health-related quality-of-life, and (4) serum oxidative stress markers. Because median disease duration is short, the pool of ALS clinical trial participants at any given time is quite limited. Survival as an outcome measure is the gold standard for phase HI trials, but requires a large sample size. Because several new agents will soon be available for clinical testing, it is vital to reduce the number of patients required for phase II trials if these agents are to be tested in a timely, effective way. Aim 3 will evaluate alternative outcome measures to determine if their use can decrease the sample size required for ALS trials (see QALS-STAT). If CoQ 10 is effective in reducing functional decline in ALS, after phase III confirmation this knowledge will have an immediate impact on clinical practice and our understanding of ALS pathophysiology. This application is the clinical part (QALS-CLIN) of two separate, but highly coordinated units, which together constitute QALS (Clinical Trial of High Dose CoQ 10 in ALS). A separate R01 grant proposal (QALS-STA T, PI JLP Thompson) has been submitted for conduct of the statistical operations.